These mechanisms may include mitochondrial malfunction and oncogenic signaling, such Ras and Akt [ 31, 36].
Other similarities are evident at the cellular level, particularly mitochondrial malfunction and disorganization (3– 5).
Indeed, it had been demonstrated that proteasome activity is correlated with mitochondrial malfunction and oxidative stress in a mouse model of neurometabolic disease, arguing for a role of mitochondria dysfunction in ROS-mediated proteasome activation.
Several studies show that -carnitine has a neuroprotective action in different neurodegenerative pathologies such the syndromes of Parkinson and Alzheimer, wherein mitochondrial malfunction and oxidative stress are also observed.
This disruption leads to an accumulation of mitochondrial mutations and increased levels of reactive oxygen species (ROS) (owing to mitochondrial malfunction) and cell death, and ultimately leads to PD (Fig. 1B).
In addition, aging is characterized by significant changes in gene expression, including the tissue-specific induction of oxidative stress response genes and heat shock proteins (Hsps), and these gene expression changes may represent a response to mitochondrial malfunction, oxidative stress and proteotoxicity [ 9- 13].
This is due to inhibition of the sacro/endoplasmatic reticulum Ca2+-ATPases (SERCA), release of Ca2+ from ER and acidic stores and granules, increased Ca2+ influx, and acini show cellular acidosis, enzyme activation and mitochondrial malfunction, which can eventually lead to development of (biliary) acute pancreatitis [ 20, 22– 22].
The mechanisms are considered to include microcirculatory disturbances, that block the oxygen supply, and mitochondrial malfunction that results in inadequate use of oxygen at the cellular level.
Growing evidence suggests that cancer cells exhibit increased intrinsic ROS stress, due in part to oncogenic stimulation, increased metabolic activity, and mitochondrial malfunction.
Intriguingly, the combination of a disturbed Ca2+ homeostasis and mitochondrial malfunction, although likely initiated by different mechanisms, has also been implied as an important factor in diabetic neuropathy (reviewed by Verkhratsky and Fernyhough).
We also show that growth retardation in BRAT1 knockdown cells is due to mitochondrial malfunction that causes increased ROS and decreased ATP production.
